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1 Surgical Metabolism and
Nutrition Laboratory, With progression of tumor growth, rats
demonstrate anorexia and reduced food intake, a function of meal number
and meal size. Tumor necrosis factor-
cancer anorexia; food intake regulation; feeding behavior; tumor
necrosis factor- IN TUMOR-BEARING RATS, anorexia and reduced food intake
are frequently observed. When translated to the human situation, this scenario contributes to the development of malnutrition and to a
worsening of the overall chances of survival (25).
In the pathogenesis of cancer anorexia, both central and peripheral
factors participate in determining the reduction of food intake during
tumor growth (23). Cytokines play a major role by modulating
hypothalamic feeding sites (36), modifying neurotransmitter concentrations (27), and influencing brain catecholaminergic and
serotonergic systems. Among them, tumor necrosis factor- TNF- TNF- The mode of anorexia occurrence in tumor-bearing rats may also further
strengthen the link between TNF- Animals
ABSTRACT
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ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
(TNF-), a recognized
anorectic agent, reacts with two different receptors (type I: 55 kDa;
type II: 75 kDa). We used a dimeric, pegylated 55-kDa TNF receptor
construct to test its effects on food intake, meal number, and meal
size, which were continuously measured with a rat eater meter in 16 Fischer 344 male rats injected with
106 viable methylcholanthrene
cells. When anorexia developed, rats received a subcutaneous injection
of either 0.25 mg/kg body wt of soluble TNF receptor construct (study)
or vehicle (tumor-bearing control). Before TNF inhibitor injection, no
differences were observed in food intake, meal number, or meal size
between the two groups. After the TNF inhibitor injection, study vs.
control rats significantly improved food intake as a result of an
increase in meal number and meal size. Rats also showed a significant
improvement in body weight. These data suggest that TNF-, in
addition to other cytokines, contributes to the anorexia of tumor
growth, probably mediated via the hypothalamus.
INTRODUCTION
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ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
(TNF-)
is a well-recognized anorectic agent (22, 36).
, produced by blood monocytes and tissue macrophages in response
to tumors (17), as well as by the tumor itself (13), can interact with
two distinct surface receptors with molecular weights of 55 and 75 kDa
(32). The intracellular domains of the p55 (type I) and p75 (type II)
TNF receptors differ, suggesting distinct signal transduction pathways.
In vivo studies showed improvement in the inflammatory symptoms of
rheumatoid arthritis during a 3-mo trial using the soluble TNF receptor
p75 linked to the Fc portion of human IgG (18), whereas stimulation of the p55 TNF receptor induced activation of coagulation and fibrinolysis in baboons (34).
acts directly on the central nervous system to produce its
anorectic effect (5, 23, 36) by crossing the blood-brain-barrier (7).
Whether administered centrally or peripherally, TNF- suppresses food
intake in a dose-dependent manner (2). The central mechanisms for the
action of TNF- appear to be related to its modulatory effects on
neural activity of glucose-sensitive neurons within the ventromedial
nucleus of the hypothalamus (VMN) (8) and the lateral hypothalamic area
(LHA) (24), and to the stimulation of hypothalamic
PGE2 synthesis (4), which in turn
stimulates the release of corticotropin-releasing factor associated
with an anorectic effect (33).
and cancer-associated anorexia.
Daily food intake (FI) is a function of the number of meals per day
(MN) and the size of each meal (MZ) (i.e., FI = MN × MZ). Thus
the reduction of FI during anorexia can be accomplished via a reduction
of MN and/or MZ, simultaneously or via different temporal occurrences.
The aims of this study were 1) to
measure FI and feeding indexes of MN and MZ at the onset of cancer
anorexia and 2) to test the effect
of a TNF inhibitor, a soluble dimeric, pegylated 55-kDa TNF receptor
construct, to ascertain whether its subcutaneous administration would
modulate feeding pattern and/or reduce anorexia by increasing FI,
thereby attenuating body weight loss.
MATERIALS AND METHODS
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ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
Male Fischer 344 rats (n = 16; Taconic, Georgetown, NY), with an initial weight of 240-260 g were housed in rat colony cages for 10 days to acclimate them to the constant study surroundings: 12:12-h light-dark cycle (lights off 1700-0500), 26 ± 1°C room temperature, and 45% relative humidity. Rats had free access to fresh, coarsely ground chow (Diet #5008; Ralston Purina, St. Louis, MO) and tap water.
General Procedures, Definition of Anorexia, and Study Design
After the acclimatization period, rats were placed in individual cages equipped with the automated computerized rat eater meter (ACREM; Fig. 1). Purina rat chow (Diet #5008; Ralston Purina) and tap water were available ad libitum. The ACREM consists of commercially available metabolic cages, in which the supplied feeding cup at the end of the feeding tunnel is replaced by an electronic scale balance and two photoelectric cells centered above the food dish. A real-time remote computerized data collection device integrates feeding activity as measured by the electronic scale and the photocells. The ACREM characterizes feeding activity of the rat by monitoring access to the food cup. A meal is defined as a bite or a series of bites preceded and followed by at least 5 min of feeding inactivity (15). The following spontaneous FI and FI-related indexes were measured continuously by the ACREM and recorded every 24 h: FI (g/day) = amount of food consumed per 24 h; MN (meals/day) = total number of meals per 24 h; and MZ (g/meal) = total amount of food consumed per each meal during 24 h. The ACREM also permits the discrimination between light- and dark-phase eating activity; however, for reasons of simplicity, we elected to show only the 24-h data. Ten days after being placed in the ACREM cages, rats received a subcutaneous injection of 0.5 ml of 406 trypan blue viable methylcholanthrene sarcoma cells into the right flank. The tumor cell suspension was prepared according to Madden and Burk (14). The given dose produces a tumor which becomes palpable ~9 days after inoculation and induces anorexia at a mean of 18 days after inoculation (1, 8, 11).
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The rats' body weights were measured daily. Tumor size was also measured daily, and tumor volume and weight were calculated with the formula for a prolate spheroid (V = 1/2ab2, where a is the longer and b the shorter dimension).
Tumor-bearing rats were defined as being anorectic after three consecutive days in which each rats' food intake was reduced by at least 1 g/100 g body wt compared with the mean daily food intake of the pretumor inoculation period, according to a modification of the definition of Chance et al. (3).
On the day the rats were diagnosed to be anorectic
(day
0), they were randomly assigned to
receive either the soluble pegylated 55-kDa TNF receptor construct or
normal saline, the vehicle. Study rats received a subcutaneous
injection of 0.25 mg/kg body wt of TNF receptor dissolved in 500 µl
of saline into the left flank, whereas control rats received 500 µl
of saline. The dimeric, pegylated soluble TNF receptor (p55) construct
was obtained from Amgen (Thousand Oaks, CA). Comprised of two
extracellular domains of the human p55 TNF receptor covalently linked
with polyethylene glycol, this compound has an extended biological
half-life and neutralizes human, baboon, mouse, and rat TNF- (29,
26). The dose employed was based on earlier studies with the same
construct in rodent models of endotoxin shock and experimentally
induced arthritis (26, 9). FI, MN, MZ, body weight, and tumor weight
were recorded daily for 7 days after injection.
Statistical Analysis and Data Handling
Data were analyzed with t-tests, general linear models, and mixed-effect models for FI, MN, MZ, and body weight. SAS, statistical software from the SAS Institute, was used for all analysis. The t-tests were used to test for daily mean differences for each of the feeding indexes. In examining the group, the day, their interaction, and the subject effects on each of the feeding indexes, SAS Procedure General Linear Model (PROC GLM) and SAS PROC Mixed Model Analysis (MIXED) were used to handle the repeated measurements and random individual rat effect. ANOVA was done by SAS PROC GLM to especially study the individual rat effect, and the mixed-effect model analysis was done by SAS PROC MIXED to study trends over time treating individual rat effects as random effects. Correlation coefficients were applied to changes in FI, MN, and MZ in the period from day
3 to
day
0. Significance is indicated in
figures and text. Figures 2 and
3 include average values of feeding indexes along with their standard errors.
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Period From Day 3 to Day 0
3 to day 0 in an attempt to more clearly document this impression. In the period
from day
3 to
day 0 of anorexia, the average linear correlation coefficient was 0.095 between FI and MN in the control group, whereas it was 0.49 between FI
and MZ (P < 0.01). This strongly indicates that the reduction of FI at the onset of anorexia is
better explained by the change in MN, whereas the reduction in MZ
occurs only later.
Pre-TNF Receptor Injection
As indicated in Figs. 2 and 3, there was no significant difference between mean feeding indexes of the study and control groups. As anticipated by the nature of randomization, there was no significant difference of the slopes between the groups.Figures 2A and 3 show linear trends in the FI change and the body weight change, and the regression analysis done by SAS PROC MIXED suggested linear regression as a reasonable model to describe the changes in FI and body weight during this period.
Post-TNF Receptor Injection
An overview of Fig. 2 shows that a significant improvement in FI occurred after TNF inhibitor injection (Fig. 2A). This was a result of a significant improvement in MN (Fig. 2B) and a smaller but significant improvement in MZ (Fig. 2C) in the study group. Significant time trends and group effects on FI, MN, MZ, and body weight occurred via rates of change and mean levels. The occasional rise in MN shown in Fig. 2B on day 3 for the control group and day 5 for the study group was mainly the result of missing values. The changes in FI, MN, MZ, and body weight were examined more closely and are summarized as follows:Food intake. As shown in Fig. 2A, FI in the control group continued to decrease, whereas it significantly improved in TNF-inhibitor-treated rats.
Although t-tests for mean difference
between the groups showed statistical significance only from
day 5 after the injection, further analysis using SAS PROC MIXED was done to
incorporate nonzero correlation among repeatedly measured FI and
individual rat effect. The variable "day" was used as a
regression variable in SAS PROC MIXED to understand the time trends
among repeated measurements. Treating the individual rat effect as a
random effect and using autoregressive error with lag one,
AR(1), the day effect, and the group × day
interaction effect were found to be significant with
P < 0.001. The regression equations
were estimated as 15.932 1.118 × day for the control
group and as 13.893 + 0.116 × day for the study group. The linear
coefficient for the control group, 1.118, was significant
(P < 0.001), whereas the linear
coefficient for the study group, 0.116, was not significant
(P = 0.300).
Several options for the covariance structure, such as AR(1), compound symmetry, and unstructured autocorrelation have been examined, and the AR(1) structure was determined to be the best one on the basis of Akaike's Information Criterion and Schwarz's Bayesian Criterion, as well as on the fact that it is natural for this kind of data to have correlations that are larger for nearby times than for far-apart times.
Meal number. The changes in mean daily MN during the postinjection period are shown in Fig. 2B and indicate a significant improvement in TNF-inhibitor-treated rats compared with controls.
Because of a large within-group variability (P = 0.001; ANOVA) there was no significant mean difference between the groups on a daily basis. ANOVA done by SAS PROC GLM indicated a significant within-group variability (P = 0.001). However, noting that the average daily meal number indicated a curvilinear trend and that the linear fit is reasonable only for half of the 16 rats in the study, a mixed-effect model with quadratic and linear trends was applied. The model with AR(1) covariance and the random rat effect was used treating day and day × day as regression variables. The day × day effect was significant (P = 0.007), and the day effect had a P = 0.08. No interaction term was found to be significant in the test for fixed effects, but the examination of individual regression equations below indicates interaction between day × day and group.
The estimated regression equations for the model with the linear and
the quadratic time trends were 11.080 + 1.335 × day 0.258 × day × day for the control group and 13.019 + 0.847 × day 0.155 × day × day for the
study group, where the regression coefficients of 1.335, 0.847, and
0.155 are not significantly different from zero. The coefficient
for the quadratic term for the control group, 0.258, was
significant (P = 0.017). It implies that the daily mean meal number remains constant for the study group,
whereas it decreases with quadratic time trend in the control group.
Meal size. The changes in mean daily MZ during the postinjection period are presented in Fig. 2C and show a significant improvement in TNF-inhibitor-treated rats compared with controls.
Again, because of a large within-group variability (P < 0.001; ANOVA), there was no significant mean difference between the groups. Treating day as a regression variable, a mixed-effect model with quadratic and linear time trends was applied, and there was no indication of a significant quadratic effect. For a model with only the linear time trend and interaction effect, SAS PROC MIXED indicated day and day × group as significant effects (P < 0.0001 and 0.041, respectively).
The estimated regression equations are 1.165- 0.068 × day
for the control group and 1.090-0.023 × day for the study
group, where the linear coefficient of 0.023 for the study group
was not significantly different from zero. The coefficient for the linear term for the control group, 0.068, was significant
(P < 0.001). The results from the
mixed-effect model analysis imply that the daily mean MZ remains
constant for the study group, but it decreases with a linear time trend
in the control group. Although Fig. 2C
indicates a curvilinear pattern for the control group, the nonlinear
terms were not significant mainly because of a large rat-to-rat variability.
Body weight. Figure 3 shows the change in body weight during the postinjection period and indicates a significant improvement in TNF-inhibitor-treated rats compared with controls. As outlined for the MN and MZ, there was no significant mean difference between the groups (P < 0.001; ANOVA).
Body weight decreased over time in the control group, whereas it
increased in the study group. The mean average increase rate of 1.48 ± 0.71 g/day showed a significant linear time trend
(P = 0.050) and a moderately
significant interaction effect (day × day × group;
P = 0.078). The estimated regression
equations are 351.634 + 4.683 × day 0.582 × day × day for the control group and 351.788 + 1.048 × day + 0.040 × day × day for the study group, where
coefficients for the linear and quadratic terms for the control group,
4.683 and 0.582, were significant
(P = 0.029 and 0.025, respectively).
The regression coefficients of 1.048 and 0.040 for the study group were
not significant for this model because of overfitting. When a linear
time trend model was fitted for the study group rats (see Fig. 3), the
regression equation was estimated as 351.289 + 1.372 × day, and
the linear coefficient was highly significant
(P = 0.002).
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DISCUSSION |
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ABSTRACT
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MATERIALS AND METHODS
RESULTS
DISCUSSION
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The findings from this experiment in male Fischer 344 rats show
1) that during the onset of anorexia
(day
3 to
day
0), FI decreases by an exclusive
decrease in MN, joined only later by a decrease in MZ, suggesting an
independent and temporally differential effect of the tumor;
2) that with the onset of anorexia
(day
0), in the controls there is a
progressive decrease in FI via a decrease in MN and MZ, resulting in a
decrease in body weight; and 3) that inhibition of TNF- activity by a soluble p55 TNF receptor construct results in improved FI via both MN and MZ, leading to improved body weight.
The role of cytokines in the development of cancer anorexia has been
repeatedly shown in experimental animal models (11, 20). Cytokines
initiate a cascade of events that ultimately leads to a state of
wasting, malnourishment, and eventually death. The improvement of FI
(19), the normalization of metabolic changes (10), and the restoration
of body weight (19) that has been reported after tumor removal support
this hypothesis. TNF- is involved in the anorexia associated with
tumor growth, as suggested by the use of anti-TNF antibodies in
anorectic tumor-bearing rats, resulting in enhanced food intake (28).
In our study, after the injection of the TNF inhibitor in anorectic
tumor-bearing rats, we observed a significant improvement in FI as a
result of improvements in both MN and MZ. The effects of TNF- and
TNF inhibition on the feeding indexes of MN and MZ have been previously
investigated (30, 31), showing a main effect on MZ. Our present data
confirm and extend these reports by showing that TNF inhibition during
tumor growth improves MZ as well as MN. The apparent difference between
our results and those previously reported is likely a result of the
different settings of the studies; i.e., we used tumor-bearing rats in
which the anorexigenic stimulus of TNF- is chronically exerted,
whereas previous studies tested normal rats that acutely received
pathophysiological concentrations of TNF-.
A peculiar feature of the beneficial effect of the dimeric, pegylated
55-kDa TNF receptor construct on the anorexia of cancer is its delayed
occurrence. In our study, tumor-bearing rats treated with the TNF-
inhibitor gradually improved FI. A likely explanation for this
phenomenon might lie in the interaction existing between TNF- and
its receptor on target organs. At the onset of anorexia, it might be
assumed that most of the TNF receptors are bound with the soluble
TNF-. Our pegylated construct does not have any effect on the
complex TNF-/TNF receptor, but it reduces the amount of soluble
TNF- available for binding. It is therefore conceivable that when
new TNF receptors are made available on the cell surface or within a
group of neurons, according to their turnover rate, fewer TNF-
molecules can bind to them. This in turn might cause the delayed
improvement of anorexia observed in our rats.
In our experiment, study rats also showed a significant improvement in
body weight compared with control rats. This is subsequent to the
improved FI and may also reflect the role of TNF- in tumor-induced acceleration of skeletal protein net degradation and reduction of
muscle protein synthesis (17). TNF- also acts as a tumor growth
factor (6) by promoting angiogenesis (21); study rats showed a
reduction of the mean tumor size, although nonsignificant, by the end
of this relatively short study. Further studies using a different
protocol for administration of the TNF receptor construct may clarify
this point.
This study provides a further step in the understanding of the pathogenesis of a multifactorial syndrome such as cancer anorexia, gives further insight into the comprehension of the mechanisms that regulate feeding activity, and helps to better elucidate the role of the p55 TNF receptor. Whether the soluble pegylated 55-kDa TNF receptor-construct can be considered as a potential future drug to ameliorate anorexia in cancer patients remains to be evaluated.
Perspectives
The target organs for TNF- in regulating feeding activity still need
to be better characterized. Thus our present data cannot be related to
any specific effect on a selective site. However, the hypothalamus
plays a major role in the regulation of FI and contains TNF-sensitive
neurons located in different areas, including the VMN and LHA (8, 24).
It is therefore likely that the observed effects might be, at least in
part, mediated by these hypothalamic sites. Also, the enhancing effect
of the TNF inhibitor on MN and MZ in anorectic tumor-bearing rats is
consistent with the hypothesis that the VMN and LHA influence these
feeding indexes (16). It is now recognized that the brain is provided
with a redundant series of neuroimmunoendocrine systems to maintain the homeostasis of FI, i.e., the close and inverse relationship between MN
and MZ (35). These systems appear to involve a number of anatomically
and functionally related brain areas and nuclei, including the VMN and
the LHA. In the past, we showed 1)
that the size of a meal is related to LHA-dopamine concentrations (16) and 2) that the onset of cancer
anorexia is associated with low dopamine and high serotonin levels in
the VMN (1). Furthermore, the injection of a serotonin receptor blocker
into the VMN at the onset of cancer anorexia reverses the reduced FI by
an exclusive increase in MN (12). These findings, together with the
observation that reduced FI at the onset of cancer anorexia is brought
about by reduced MN, strongly suggest an early influence of tumor
associated cytokines on the VMN of the hypothalamus, thus accounting
for the reduction in MN, which is then followed by the involvement of
the LHA and the reduction in MZ.
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ACKNOWLEDGEMENTS |
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The work presented in this manuscript was supported in part by National Cancer Institute Grant 70239.
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FOOTNOTES |
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The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. §1734 solely to indicate this fact.
Address for reprint requests and other correspondence: M. M. Meguid, F.A.C.S., Dept. of Surgery, Univ. Hospital, SUNY Health Science Center, 750 East Adams St., Syracuse, NY 13210 (E-mail: meguidm{at}mailbox.hscsyr.edu).
Received 26 October 1998; accepted in final form 26 May 1999.
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ABSTRACT
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MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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